J. Org. Chem. 1992,57, 504-511
504
Enolization of Thioesters by ChxzBC1/Et3N. A representative example of enolization of S-tert-butyl thioacetate is described as follows. To a stirred solution of ChxzBCl(1.2 mL, 5.5 "01) and EbN (0.77 mL, 5.5 "01) in CCl, (15 mL) cooled at 0 "C was added an internal standard, benzene (0.5 mmol), followed by the slow addition of S-tert-butyl thioacetate (0.78 mL, 5 mmol). The molarity of the solution was adjusted to 0.3 M. The reaction mixture was stirred for 1h and worked up as described for ketones. Analysis of the olefinic proton by 'H NMR suggests >95% enolization. Enolization of &Keto Ester by ChxzBC1/Et3N. The enolization of ethyl acetoacetate is described as follows. To a stirred solution of ChxzBC1(1.2 mL, 5.5 mmol) and EbN (0.77 mL, 5.5 mmol) in CC14 (15 mL) cooled at 0 "C was added an internal standard, benzene (0.5 mmol), followed by the slow addition of ethyl acetoacetate (0.64 mL, 5 m o l ) . The molarity of the solution was adjusted to 0.3 M. The reaction mixture was stirred for 1 h and worked up as described previously for ketones. Analysis by 'H NMR showed 94% enolization. General Procedure for t h e Aldolization with Benzaldehyde. To a solution of enolborinate in diethyl ether generated from 5 mmol of the carbonyl compound using ChxzBC1/EbN as described above was added benzaldehyde (0.51 mL, 5 mmol) dropwise at -78 "C, and the mixture was stirred for 2-3 h. Then the reaction mixture was allowed to warm up overnight slowly to attain the room temperature. (Later we discovered that the reaction is essentially complete in 2-3 h at -78 "C, so that the slow warmup to 25 OC is unneccessary. Both procedures give the same results.) Then 10 mL of methanol was added to dissolve the precipitate (EhNHCl), 1.7 mL of HzOZ(30%) was added at 0 "C, and the mixture was stirred for 5-6 h at 25 "C. The solvent was then removed by water aspirator and the reaction mixture was extracted with ether, washed with dilute HC1 and water, and dried over anhyd Na2S04. The solvent was removed and the
products were analyzed as such by lH NMR to determine the syn/anti ratio. In the case of carboxylic acids, after the aldolization, 5 mL of H,O waa added to the reaction mixture at 25 "C. and the reaulth &e was stirred for 30 min. The products were then extra& with aqueous NaHC03, neutralized with 20% HC1, extracted with ether, dried over anhyd NazS04,concentrated, and analyzed by 'H NMR.
Acknowledgment. We gratefully acknowledge financial support from the United States Office of Naval Research, which made this research possible. Registry No. 1, 22086-34-6; 2, 137495-66-0; 3, 137495-67-1;
4,36140-19-9; 5, 58335-30-1; 6, 137495-682; BMS, 13292-87-0; 9-BBN, 280-64-8; CH&OCH3,67-64-1; CH3COCH&H3,78-93-3; CH3CHzCOCHzCH3,96-22-0; PhCOCHZCHS, 93-55-0; CHSCHZCHZCHO, 123-72-8; PhCHzCHO, 122-78-1; (CHJZCHCHO,7884-2; DC~HI~CHO, 2043-61-0; CH&(OBChx,)CH3,137495693; CH~=C(OBC~XZ)CHZCH~, 137495-70-6; (E)-CH&H=C(OBChxz)CHzCH3, 120312-96-1; (E)-CH3CH=C(OBChxZ)Ph, 120312-92-7; CH3CHZCH=CH(OBChxz), 137495-71-7; (2)PhCH=CH(OBChxz), 137495-72-8; (CH3)2C=CH(OBChxZ), 137495-73-9;c-C6Hlo=CH(OBChxz),137495-740;ClBHz.SMe2, 63348-81-2; CH&HZCOOH, 79-09-4; CH3(CHZ)&OOH, 142-62-1; PhCHZCOOH, 103-82-2;(CH3CHzC0)20,123-62-6;CH3COSC(CH3)3, 999-90-6; CH,COSPh, 934-87-2; CH3COCHZC02C2H5, 141-97-9; CH&H=C(OBChx2)2, 137495-75-1; CH&CHZ)&H= C(OBChxz)z, 137495-76-2; PhCH=C(OBChxZ)z, 137495-77-3; CH~CH=C(OBC~XZ)OCOCZH 137495-78-4; ~, CH2=C(OBChxZ)SC(CH3)3, 137495-79-5; CHz=C(OBChxz)SPh, 137495-81-9; 137495-80-8; (Z)-CH~C(OBC~X~)=CHCO~C~H~, PhCHO, 100-52-7; (E)-PhCH=CH(OBChxz), 137495-82-0; CYclohexene, 110-83-8.
Chiral Synthesis via Organoboranes. 33. The Controlled Reaction of B -Alkyldiisopinocampheylboraneswith Aldehydes Providing a Convenient Procedure for the Enantiomeric Enrichment of the Boronic Ester Products through Kinetic Resolution Navalkishore N. Joshi,'" Chongsuh Pyun,lbVerinder K. Mahindroo,lCBakthan Singaram,ld and Herbert C. Brown* H.C. Brown and R. B. Wetherill Laboratories of Chemistry, 1393 Brown Building, Purdue University, West Lafayette, Indiana 47907-3699 Received July 2, 1991 Controlled treatment of B-alkyldiiipinocampheylborane(3a),IpczBR*, obtained by asymmetric hydroboration of appropriate olefin, with aldehydes produces chiral boronate esters (5) having enantiomeric purities markedly higher than those of the substrate. A systematic study of the reaction revealed that the intermediate borinic esters (4) are being kinetically resolved. Since asymmetric hydroboration of alkenes with diisopinocampheylborane (1) provides predominantly the diastereomer that reacts faster with aldehydes, the reaction furnishes in situ enantiomeric enrichment of the products. Thus, B-alkyldiisopinocampheylboranes(3a) possessing 81-96% ee are readily converted into borinic esters (5) including 2-butyl, 3-hexyl, and ero-norbornyl derivatives of 199% ee. Successful efforts were also made to extend the scope of asymmetric hydroboration-kinetic resolution to representative cyclic dienes making available pure enantiomers of exo-5-norbornenyl-and 3-cyclohexenylboronic esters. Hydroboration is one of t h e fundamentally novel reactions in organic chemistry. In recent times a variety of procedures have become available for the enantioselective version of this reaction. They include chiral organoboranes derived from terpenesr2 Masamune's reagent,3 a n d a ~~
~
(1) (a) Postdoctoral research associate on a grant from the Office of Naval Research. (b)Department of Chemistry, Sogang University, Seoul, Korea. (c) Postdoctoral research associate on a grant from the National Institutes of Health. (d) Department of Chemistry, The University of California, Santa Cruz.
0022-3263/92/1957-0504$03.OO/0
modestly successful catalytic procedure involving chiral transition metal complexes." All of these routes transform prochiral alkenes to t h e corresponding chiral alcohols. However, t h e reagents derived from (+)- and (-)-a-pinene (2) Brown, H. C.; Vara Prasad, J. V. N.; Zaidlewim, M.J. Org. Chem. 1988,53, 2911 and references cited therein. (3) Masamune, S.; Kim, B. M.;Peterson, J. S.; Sato, T.; Veenstra, S. J. J. Am. Chem. SOC. 1985,107,4549. (4) Brown, J. M.;Lloyd-Jones, G. C. Tetrahedron Asymmetry 1990, 1, 869 and references cited therein.
0 1992 American Chemical Society
J. Org. Chem., Vol. 57, No. 2, 1992 505
Chiral Synthesis via Organoboranes have given a new dimension to the scope of asymmetric hydroboration, making accessible chiral organoboranes which are readily transformed into an array of pure
enantiomer^.^
'1
dl
'2
d2
The discovery of the fmt enanticeelective hydroborating reagent? diisopinocampheylborane (IpczBH, 1) marked the beginning of a practical nonenzymatic asymmetric synthesis. The reagent provided 51437% enantiomeric excess (ee) in the hydroboration of cis-disubstituted alkenes. Later on, the availability of enantiomerically pure l'jband modified reaction conditions significantly improved the resulta.& The reaction of 1 with more hindered olefins, however, is sluggish and proceeds with partial displacement of cy-pinene from the reagent. These difficultiesprompted us to explore monoisopinocampheylborane (IpcBH2,2). The moderate steric requirement of 2 permitted smooth hydroboration of trans-disubstituted as well as trisubstituted alkenes in 53-100% ee.7a-c cis-alkene
1-
R*B/x 'Ipc
, 2
nisubstituted or
am-alkene
R*BIpcz
We subsequently discovered*that treatment of the intermediates 3a and 3b with an aldehyde regenerated the chiral auxiliary, a-pinene (eq 2). The resulting boronic esters (5) could be easily converted into the corresponding chiral monoalkylboranes which proved to be the starting point for a variety of RCHo m
[
,OCH$ R*B,~~ 4
]
Results and Discussion Isopinocampheylboranes react with aldehydes and ketones liberating the 3-piny1group as a-pinene, presumably via a cyclic mechanism (eq 3). In the case of B-alkyldiisopinocampheylboranes (3a), the reaction with simple aldehyde proceeds stepwise, giving successively borinic (4) and boronic (5) esters. The first step of the reaction is relatively fast, whereas the second one is comparatively slow (eq 4).
(1)
3 a , X=Ipc 3 b , X = H
3a/3b
problem encountered with 3a was the sluggish reaction with aldehydes. The present study was undertaken to overcome these difficulties and also to understand the reaction between 3a and aldehydes. The investigation provided us with some unexpected observations regarding the reaction mechanism. The most gratifying aspect was the finding that the intermediate diastereomeric borinic esters (4) were kinetically resolved, thereby leading to a simple in situ procedure for enantiomeric enrichment of the products, viz.boronic esters (5). A part of the present study was also devoted to extending the scope of asymmetric hydroboration for hitherto unreported cyclic dienes.
R*B(OCH&
(2)
5
With the growing synthetic utility of chiral organoboranes, we learned to upgrade the enantiomeric purity of the key intermediates, 5, to 299% ee. In the case of the products arising from 2, direct crystallization of 3b itself proved to be the method of choice.Ic The enantiomeric enrichment of the product from I, however, was achieved tediously at the later stages.1° An additional (5) For pertinent reviews, see: (a) Brown, H. C.; Jadhav, P. K.; Singaram, B. Enantiomerically Pure Compounds via Chiral Organoboranes In Modern Synthetic Methods; Scheffold, R., Eds.; Springer-Verlag: Berlin Heidelberg, 1986; Vol. 4, p 308. (b) Brown, H. C.; Singaram, B. Acc. Chem. Res. 1988,21, 287. (c) Brown, H. C.; Ramachandran, P. V. Pure Appl. Chem. 1991,63,307. (6) (a) Brown, H. C.; Ayyangar, N. R.; Zweifel, G. J.Am. Chem. SOC. 1964,86,397. (b) Brown, H. C.; Yoon, N. M. Zsr. J. Chem. 1977,15,12. (c) Brown, H. C.; Desai, M. C.; Jadhav, P. K. J. Org. Chem. 1982,47,5065. (7) (a) Brown, H. C.; Yoon, N. M. J. Am. Chem. SOC. 1977,99,5514. (b) Brown, H. C.; Jadhav, P. K.; Mandal, A. K. J. Org. Chem. 1982,47, 5074. (c) Brown, H. C.; Singaram, B. J.Am. Chem. SOC. 1984,106,1797. (8)Brown, H. C.; Jadhav, P. K.; Desai, M. C. J. Am. Chem. SOC. 1982, 104,4303. (9)(a) Brown, H. C.; Singaram, B.; Cole, T. E. J.Am. Chem. SOC.1985, 107,460. (b) Brown, H. C.; Bakshi, R. K.; Singaram, B. J.Am. Chem. SOC. 1988,110,1529. (c) Brown, H. C.; Joshi, N. N.; Pyun, C.; Singaram, 1989,111, 1754. (d) Brown, H. C.; Salunkhe, A. B. J. Am. Chem. SOC. M.; Singaram, B. J. Org. Chem. 1991, 56, 1170. (10) (a) Brown, H. C.; Vara Prasad, J. V. N. J. Org. Chem. 1986,51, 4526. (b) Enantiomeric upgradation by crystallization: boronic acid of 290% ee was dissolved in a minimum volume of EtOH and then diluted
with twice the volume of degassed water. The resulting suspension was warmed (50-70 "C) until a clear solution was obtained and allowed to stand at ambient temperature to obtain crystalline boronic acid of 299% ee. The product was dried at water aspirator until constant weight (60-70460 recovery); Joshi, N. N. unpublished results.
CH3CH0 m R*B(OEt)Ipc 6-8 h
3a
CH$HO 2-8 days *
R*B(OEt)Z
(4)
5
4
R* = 2-butyl, 3-hexyl, exo-norbomyl,etc.
In order to investigate the structural effects of representative aldehydes in the reaction, 3a (R* = 2-butyl) was selected as the substrate. A standard solution of the organoborane in THF was obtained by hydroboration& of cis-Qbutene with dIpc2BH(derived from (+)-a-pinene) in THF at -25 "C. Portions of the stock solution were treated with 2 equiv of selected aldehydes at ambient temperature, and progress of the reactions was monitored by llB NMR. It was found that the reaction was slowest with CH3CH0. There was a small, but significant, difference in the reactivity of (CH3)&HCH0 and PhCHO. Remarkably, the reaction with CC13CH0was much faster than that with other aldehydes examined! Mikhailov proposed a cyclic mechanism for the reduction of benzaldehyde by reaction with trialkylboranes (eq 5).lla In the present investigation, our results can also be
L
J
rationalized in terms of a concerted mechanism similar to that involved in the Diels-Alder reaction. In the DielsAlder reaction, the presence of electron-withdrawing groups in the dienophile favors the cycloaddition. Alternatively, the presence of electron-donating groups on the dienophile hinders the reaction. The opposite effect is generally observed by introducing such groups into the (11) (a) Mikhailov, B. M.; Bubnov, Yu. N.; Kieselev, V. G. J. Gem Chem. USSR 1966, 36, 65. (b) Midland, M. M.; Zderic, S. A. J. Am. Chem. SOC. 1982,104,525. (c) For an examination of the rates of reaction of IpqBCl and IpczBalk with benzaldehyde; see: Brown, H. C.; Ramachandran, P. V.; Chandrasekharan, J. Organometallics 1986, 5, 2138. (12) Sauer, J.; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980,19, 779.
506 J. Org. Chem., Vol. 57, No. 2, 1992
Joshi et al.
Table I. Enantiomeric Purities of the Boronic Esters (5) I Obtained by the Treatment of B -Alkyldiisopinocampheylboranes(3a) with PhCHO
R*BIpcz 38
PhCHO
R*B(OCHzPh)Ipc 4
PhCHO
RtB(OCH2Ph)z 5
ratiob entrv 1 2
R* 2-butyl
time? d
4
4d
3
3-hexyl
9
4 5
exo-norbornyl
6 3d
0 20 0 20 0
2
20
1.5
30
3
6 7
5 100 80 100 80 100 80 70
% eee of 5
93d >99 91d >9gd 81d 90 93
All reactions were carried out as 1.0 M in THF and at ambient temperature. bApproximate, established by llB NMR. Of the corresponding R*OH obtained by the oxidation of 5. Represents the initial induction. 4 and 5 were not separated prior to oxidation. a
TIME, h
Figure 1. Rate study of the reaction between (2-Bu)BIpcz and representative aldehydes; 1.0 M THF, 25 f 1 OC. ( 0 )CH3CH0, (A)(CHJZCHCHO, (m) CC13CH0, ( 0 )PhCHO, (0) PhCHO + 5 mol % BF3-Eh0.
diene. Finally, the introduction of Friedel-Craft catalysts into the reaction mixture results in electronic shifts, which can markedly alter the reaction rate. In the reaction of aldehydes with the alkylisopinocampheylborinic esters, R*IpcBOEt, that produces the optical upgrade that is the subject of this study, we must go through a similar transition state (eq 6).
products (3) involves a simple treatment with an excess of aldehyde. During the above-mentioned rate study, however, we inadvertently worked up one of the reaction mixtures involving the treatment of 2-BuBIpc2 with PhCHO after -90% completion. At that stage of the reaction, llB NMR indicated a -1:4 mixture of the unreacted intermediate (benzylborinate, 6 53 ppm) and the product (dibenzylboronate, 6 31 ppm). The reaction mixture was therefore extracted with 3 N NaOH to isolate boronic acid from the reaction mixture. Oxidation of the isolated boronic acid with alkaline Hz02provided optically active 2-butanol. The enantiomeric excess (% ee) of the product was determined by capillary GC analysis of its MTPA ester. To our surprise, the % ee of 2-butanol was significantly higher than that of the starting material, 2-BuBIpc2! To confirm the results, the borinic acid remaining in the organic phase following the extraction of the boronic acid with 3 N NaOH was isolated and oxidized. Indeed, the % ee of 2-butanol from the borinic acid was very much lower (eq 7). PCHzPh
PhCHO PhCF$O
-79
(6) d
R
*
Factors which increase the electrophilicity of the boron atom, such as a chlorine substituent on boron, should favor the rate of reaction. Factors which increase the electron deficiency on the carbonyl carbon should enhance the rate of transfer of the &hydrogen and favor the reaction. This provides a simple interpretation which rationalizes the phenomena we have observed of the factors which influence the rate of the reaction leading to the enantiomeric enrichment of the boronic ester products. For example, as pointed out above, the reaction of chloral with R*IpcBOEt is much faster than the rate with benzaldehyde. Similarly, the rate of reaction of benzaldehyde-BF3 is considerably greater than the reaction with free benzaldehyde. Finally, the reaction of IpczBCl with ketones is far faster than the corresponding reactions with B-Ipc-9-BBN.llC The rate study of a related derivative, 2-butyldiisopinocampheylborane(2-BuBIpc2),with representative aldehydes is summarized in Figure 1. Kinetic Resolution. The routine procedure* for preparing chiral boronate esters (5) from the hydroboration
@a,R+ = 2-Bu)
rk (-20%) 71%ee
93% ee
B(OCH2Ph)Z (7)
+
(-80%) 299% ee
It appeared that we had encountered kinetic resolution during the displacement reaction. This unexpected finding appeared to be a promising procedure for an in situ enantiomeric enrichment of boronic esters. The reaction was therefore examined for a few other diisopinocampheylborane derivatives (3a) and appeared to be generally applicable (Table I). It appeared that the two diastereomers (A andB) of the intermediate borinic ester react with an aldehyde at different rates. To examine this hypothesis, we proceeded to prepare the two diastereomers by independent methods and to study separately their reaction with PhCHO. OCHzPh I
(RRj-isomer, A
f)CH2Ph
(SJ?)-isomer, B
The R,R diasteromer (A) of 93% ee was obtained by asymmetric hydroborationk of cis-2-butenewith dIpc2BH,
J. Org. Chem., Vol. 57, No. 2, 1992 507
Chiral Synthesis via Organoboranes Scheme I. R,.R Diastereomer Reacts Faster, Leading to the Optical Upgradation of Boronic Ester
Scheme 11. S,R Diastereomer Reacts Slower, Leading to the Optical Downgradation of Boronic Ester H
(93% ee)
1.0eq PhCHO
25 OC, 6 h
. )
I
I
+
c
+
)sBXIF
25 OC, 72 h
(804b eel
r
B (3.5%)
-
OCHzPh
OCHzPh
I
I
PhCH@H
A (96.5%)
0 . 9 q PhCHO
Et@, -350Cb
OCH2Ph
OCH2Ph
1' ,+B'Ipc
IpcBH,
+
OCHzPh
B (OCHzPh),
product (>99% ee)
+
y8'"
?CHzPh
unnacted (71%~~)
followed by treatment with 1equiv of PhCHO. This is a relatively fast reaction. Subsequent reaction of A with an additional 0.9 equiv of PhCHO and analysis of the reaction mixture was carried out as described above. The enantiomeric excess of the borinic ester produced was 199% and that of the unreacted borinic ester was only 70%. The results implied that the major diastereomer A in the experiment was the faster reacting component, thereby enhancing the enantiomeric purity of the product, i.e., boronic ester (Scheme I). To confirm the above results further, the reation of the S,R diasteromer (B) with PhCHO was examined. This diastereomer could be easily prepared7bicfrom trans-2butene. Hydroboration of trans-2-butene with dIpcBH2 (from (+)-a-pinene) gave a dialkylborane, 2-Bu(BH)Ipc, which upon treatment with PhCH20H provided B of 80% ee. The reaction of B with PhCHO was significantlyslower than that of A. Separation of the product (boronic ester) from the unreacted borinic ester, oxidation of each component, and determination of 9% ee of the resulting 2-butan01 was carried out as usual. As expected, the product boronic ester had been downgraded (to 78% ee) and the unreacted borinic ester upgraded (to 91% ee). Here the major isomer, S,R reacts slower than the minor isomer, R,R, thereby upgrading the unreacted borinic ester. However, the extent of upgradation is only moderate due to the fact that the R,R diastereomer, though being faster reacting, is present as a minor impurity in the mixture. This c o n f i our earlier conclusion that R,R is the faster reacting diastereomer (Scheme 11). Optimization of the Reaction Parameters. Having established the above kinetic resolution as a valuable tool for upgrading the enantiomeric purity of boronic esters from hydroboration of appropriate alkenes with Ipc2BH, we sought to optimize the procedure. A study was undertaken for evaluating the solvent effect, the structure of the aldehyde, and the stoichiometry of the reactants. To begin with, it was observed that enantiosebction can be slightly improved (3-4%) by performing the hydroboration with Ipc2BH in EhO rather than in THF. This finding is in accord with an earlier observation68that better results are realized by performing hydroboration in diglyme rather than in THF. The use of EhO as the solvent proved additionally advantageous in our study since the subsequent step (Le., treatment with aldehyde) could be carried out in the same solvent. In fact, the reaction of 3a with PhCHO was faster in EgO than in THF. The optimization of the kinetic resolution was studied in detail using 3a (R* = exo-norbornyl) because norbornene pro-
llnrwxd (91% ee)
product
(78% ce)
Table 11. Examination of Representative Aldehydes for Kinetic Resolution
(81% ee)
entry 1 2 3
4
isdated upon -90% completion RCHO CH3CHO (CHS)&HCHO CC13CH0 PhCHO
(8340%ee)
h 48 36
% eec
12
86 87 83
36
90
All reactions were carried out as 1.0 M in THF and at ambient temperature. bBased on approximate estimation by llB NMR. ODetermined by the capillary GC analysis of the corresponding MCF derivative.
vides a product with lower % ee than is achieved with the other cis-alkenes. A 0.5 M solution of exo-NrbBIpc2was treated with 2 equiv of representative aldehydes, and the reaction was monitored until -90% complete. The product (boronic ester) was extracted with 3 N NaOH and oxidized with H202,and the % ee of the resulting exonorbomeol determined. All the aldehydes tested, with the exception of CCl,CHO, provided significant kinetic resolution. Best results were realized with PhCHO, which converted ezo-NrbEhpc2of 81% ee to ex0-NrbB(0CH~Ph)~ of 93% ee (entry 4,Table 11). Our next task was to establish the optimal stoichiometry of R*BIpc2and PhCHO and also to examine the effect of BF3-Eh0 as a catalyst in the reaction. As expected, a decreased amount of PhCHO provided improved enantiomeric enrichment of the boronic ester (Table 111). In fact it was possible to obtain 199% ee for exo-NrbB(OCH2Ph)2,albeit with a modest 50% conversion. Keeping in view the sluggish reaction rates of other R*BIpc2with aldehydes, the effect of BF,-Et20 as the catalyst was also examined. The use of 1mol % ' of the catalyst significantly enhanced the reaction rate as well as the chemical conversion. Interestingly though, the addition of BF3*Eh0 at the beginning of the reaction proved detrimental for the kinetic resolution (entry 5, Table 111). The desired result was achieved, however, if the catalyst was added at the second stage of the reaction, that is, after the formation of the borinic ester (entry 6, Table 111). An explanation for the difference could be derived from our earlier observation during the reactions involving CC13CH0. Whereas the reaction of R*BIpc2 with simple aldehyde
Joshi et al.
508 J. Org. Chem., Vol. 57, No. 2, 1992
proceeds in two stages (that is, sequential elimination of each of the two isopinocampheyl groups), the same reaction with CC1,CHO or in the presence of BF3.Et20 provides random distribution of products (eq 8). In other words, R'BIFz 3a
cc13m0('
or CH3CH0 + 1 mol 9% BF,
R*BIpcz
+ +
R*B(OCH$)I~C
(8)
R*B(OCH$)2
the much faster reactions involving CC1,CHO or CH3CH0 + 1 mol % BFBare much less selective than the slower reactions with simple aldehydes. Asymmetric Hydroboration of Cyclic Dienes. Whereas the hydroboration of acyclic dienes is simple and predictable, the hydroboration of cyclic diene is intricately goverened by the structure of the diene and the reagent. Hydroboration of 2,5-norbornadiene with a hindered (e.g. Sia2BH)13"as well as an unhindered reagent (e.g. 9BBN)13b provides a statistical mixture of monohydroborated, dihydroborated, and unreacted diene. On the other hand, 1,3- and 1,4-cyclohexadienes can be hydroborated with either reagent to obtain predominantly the monohydroboration product. Surprisingly, the hydroboration of 1,5-cyclooctadiene yields predominant dihydroboration with SiazBH as well as 9-BBN. Thus, these three dienes exhibit three different behavior patterns in hydroboration. Before we began the present study, only the chiral boronate esters from simple alkenes were accessible. Except for 1,3-~yclohexadiene,'~ the asymmetric hydroboration of cyclic dienes has been neglected, partly due to the difficulties encountered during such attempts. Asymmetric monohydroboration of nonconjugated cyclic dienes could provide very valuable bifunctional molecules that could be further manipulated via a variety of optically active intermediates. The fmt part of our study, therefore, dealt with the hydroboration of these three representative cyclic dienes viz. 2,5-norbornadiene, l,Ccyclohexadiene, and 1,5-cyclooctadiene. Each one of these dienes, upon treatment with 1eqdv of dIpc2BHin EgO at -25 "C, gave varying amounts of white amorphous solid insoluble in the most commonly used solvents. Careful characterization revealed the products to be symmetrically substituted dihydroboration products. Analysis of the reaction mixtures following oxidation revealed that norbornadiene gave a statistical mixture of mono- and dihydroborated products, cyclohexadiene was monohydroborated predominantly, and cyclooctadiene was dihydroborated almost exclusively. Changing the solvent (Ego,THF, or n-Bu20) did not alter the product distribution significantly. The only option left for improving the yield of the desired monohydroborated product was to employ an excess of the diene. To obtain a high degree of monohydroboration for norbornadiene, at least a 400% excess of the diene was desirable. A 200% excess was sufficient to realize almost quantitative monohydroboration of the cyclohexadiene. The resulting cycloalkenylboronicesters were of 81% and 89% ee, respectively. As described for other boronic esters, the enantiomeric enrichment of the cycloalkenylboronic esters was also achieved via kinetic resolution. The use of a large excess of dienes was not a serious disadvantage since the excess is easily recovered from the reaction mixture. In the case of cyclooctadiene, a 400% excess of the diene provided 35% yield of the monohydroborated product with 43 % ee. Although the yield could doubtless be improved by using even larger excesses of the diene, we (13) (a) Zweifel, G.; Nagaae, K.; Brown, H. C. J. Am. Chem. SOC.1962, 84, 190. (b) Liotta, R.; Brown, H. C. J. Org. Chem. 1977, 42, 2836. (14) Brown, H. C.; Jadhav, P. K.; Bhat, K. S.J.Am. Chem. SOC.1985, 107, 2564.
did not explore this because of the low optical induction realized (Table IV). The boronic esters were conveniently isolated as the corresponding acids which were easily reesterified with 1,3-propanediol to obtain very stable cyclic esters viz. 1,3,2-dioxaborinanes (5a-c). Needless to emphasize, the use of 'Ipc2BH (derived from (-)-a-pinene) would provide the opposite enantiomers of all of the products obtained in the present study (Table V).
5b
5d
5c
5e
Conclusions A careful study of the reaction between B-alkyldiisopinocampheylboranes (3a) and representative aldehydes revealed several interesting aspects of the reaction. Interestingly, the aldehydes with an electron-deficient CLVbony1 group reacted faster than the simple aldehydes. Accordingly, external activation of the aldehydes with a Lewis acid was proposed and then proved by employing BF,.EhO as the catalyst for the reaction. The most fruitful aspect of the study was the observation that the intermediate borinic esters (4) were kinetically resolved during the reaction with aldehydes. The finding was developed into a simple and efficient in situ procedure for converting the initial hydroboration products (3a) of 81-96% ee to the corresponding boronic esters (5a-e) of 199% ee. Experimental Section All moisture- and air-sensitive reactions were carried out under nitrogen atmosphere using oven-dried glassware. llB NMR, lH NMR and '3c NMR chemical shifts are in 8 relative to BF,.EhO and Me,Si, respectively. Capillary gas chromatographic analyses were carried out on a 30 m X 0.25 mm SPB-5 column. Materials. Tetrahydrofuran (THF) was freshly dietilled over sodium benzophenone ketyl. Anhydrous ether (EhO)was purchased from Mallinckrodt Inc. and was used directly. The alkenes as well as the aldehydes used were commercial products of highest purity available and were used without further purification. (-)-Menthyl chloroformate (MCF)15and (+)-a-methoxy-a-(trifluoromethy1)phenylacetic acid (MTPAA) were purchased from Aldrich Chemical Co. The latter was converted to the cor& sponding acid chloride as described.16 Rate Study of the Reaction between R*BIpc, (3a) and Aldehydes. (R)-2-Butyldiisopinopheylboranewas chosen as the representative R*BIpc2, and a 1.0 M stock solution of the compound in THF was obtained by hydroboration of cis-2-butene with dIpc2BHas described earlier.& Five 25-mL flasks equipped with rubber septa, N2 supply, and magnetic stirring bars were each charged with portions (10 mL, 10 mmol) of the above solution. To the stirred solution (maintained at 25 l OC by was added extemal cooling),the appropriate aldehyde (20 "01) dropwise. The four aldehydes selected for the study were CHSCHO (flask l),(CH&CHCHO (flask 2), CC13CHO (flak 3), and PhCHO (flask 4). To the fifth flask BF,.EhO (60 pL, 0.5 mmol) was added, followed by PhCHO (2 mL, 20 mmol) added dropwise. After stirring at 25 f 1 "Cfor 1 h, the reaction mixtures
*
(15) Weetley, J. W.; Halpern, B. J. Org. Chem. 1968, 33, 3978. (16) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
J. Org. Chem., Vol. 57, No. 2, 1992
Chiral Synthesis via Organoboranes Table 111. Enantiomeric Upgradation of Boronic Esters by Kinetic Resolution
bBIW 3 (< 2 equiv) &B(oCH2ph)2
entry
PhCHO, equiv 1.9
1 2
1.9 1.8
3
1.7 1.7f 1.7h
4
5 6
time," h 48d 36 36 24 68 12
+ unreacted borinate
ratiob borinate boronate 0
20 30
100 80
70
50
50
20 30
70 70
% eee
85 93 97 99 87 97
"The reactions were carried out as 0.5 M in EhO and at ambient temperature. bApproximate, established by IlB NMR. 'Of (lS,2S)-ero-norborneolobtained by the oxidation of the boronic acid extracted from the reaction mixture with 3 N NaOH. dThe entire reaction mixture was oxidized after 48 h and represents initial induction. e The figure in the parentheses corresponds to the hydroboration. f lmol % BF3.Eh0 was added at the beginning of the reaction. 8The final reaction mixture still had -10% of the unreactd R*BIpc2. h lmol % BF3-Eh0was added after the removal of the first isopinocamphenyl group. Table IV. Asymmetric Monohydroboration of Cyclic Nonconjugated Dienes
% excess
entry 1 2
diene 2,Bnorbornadiene
3 4 5
% yield"
% eeb
0 100
27 55 74 85 55 81 97
83
200 400 1,4-cyclohexadiene
6
0
100 200
7
8 9 10
of diene
1,5-cyclooctadiene
0
200 400
89
